The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.

Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

Alzheimer's Disease (AD) is a leading cause of morbidity. Management of AD has traditionally been aimed at symptom relief rather than disease modification. Recently, AD research has begun to shift focus towards disease-modifying therapies that can alter the progression of AD. In this context, a class of immunotherapy agents known as monoclonal antibodies target diverse cerebral amyloid-beta (Aß) epitopes to inhibit disease progression. Aducanumab was authorized by the US Food and Drug Administration (FDA) to treat AD on June 7, 2021. Aducanumab has shown promising clinical and biomarker efficacy but is associated with amyloid-related imaging abnormalities (ARIA). Neuroradiologists play a critical role in diagnosing ARIA, necessitating familiarity with this condition. This pictorial review will appraise the radiologic presentation of ARIA in patients on aducanumab.